MicroRNA networks regulate the differentiation, expansion and

suppression function of myeloid-derived suppressor cells in tumor

microenvironment

Yanping Sua, Ye Qiub, Zhidong Qiuc, Peng Qu*d

a Department of Histology and embryology, Shangdong First Medical

University, Taian, Shangdong, China. b National Engineering Lab for Druggable

gene and protein screening, Northeast Normal University, Changchun, Jilin,

China. c Department of pharmacy, Changchun University of Chinese Medicine,

Changchun, Jilin, China. d National Cancer Institute, National Institutes of

Health, Frederick, MD, USA

*Address correspondence to:

Peng Qu, Ph.D.

National Cancer Institute

1050 Boyles St., Bldg 560, Rm 12-34

Frederick, MD 21702, USA

Phone: 301-846-5692

E-mail: peng.qu@nih.gov

Key words: MicroRNA, Myeloid-derived suppressor cells, Tumor

Abstract

Myeloid-derived suppressor cells (MDSCs), one heterogeneous population of

immature myeloid cells, have suppressive function on immune response during

tumor, inflammation, infection and autoimmune diseases. The molecular

mechanism underlying expansion and function of MDSCs is becoming

appreciated to manipulate immune response in the diseases. MicroRNA

(miRNAs) as one short noncoding RNAs, are involved in regulating cell

proliferation, differentiation and maturation. However, it needs to be further

studied how miRNAs mediate the development and function of MDSC in

association with cancer and other diseases. In the review, we report and

discuss recent studies that miRNAs networks regulate the differentiation,

expansion and suppression function of MDSCs in tumor microenvironment or

other diseases through different signaling pathways. Those studies may

provide one novel potential approach for tumor immunotherapy.

Introduction

Myeloid-derived suppressor cells (MDSCs) are the progenitors of myeloid cells

with suppressive function on immune response in tumor microenvironment

(TME). In tumor bearing-mice, MDSCs are generally characterized as GR-

1+CD11b+ cells, which are further divided as two subtypes: CD11b+Ly6G-

Ly6Chigh monocytic MDSCs and CD11b+Ly6G+ Ly6Clow granulocytic

MDSCs[1, 2]. They utilize different suppressive mechanisms to inhibit the

antitumor immune response. Monocytic MDSCs regulates immune suppression

through the production of NO and arginase[3]. In contrast, the inhibition of

granulocytic MDSCs is regulated via ROS and H2O2 [4]. In patients with cancer,

there are different types of MDSCs. In general, MDSCs are characterized as

CD33+CD15+CD14-HLA-DRlow populations [5]. Many factors, such as

cytokines, growth factors and microbial products released in tumor

microenvironments have been shown to be involved in the induction and

expansion of MDSCs with suppressive activity[6, 7]. Most of these mediators

activate signaling pathways in tumor MDSCs that involve NF-κB and STATs [1,

8, 9] . Some novel regulatory mechanisms for the differentiation, expansion and

suppression of tumor MDSCs were described recently. There is emerging

evidence that microRNAs (miRNAs) cooperate transcriptional factors to

become complex regulatory networks which mediate tumor MDSCs[10, 11].

miRNAs are the abundant small, single-stranded, non-coding RNA of about 22

nucleotides. miRNAs base-paired with the complementary sequence within

target mRNAs to mediate post-transcriptional gene repression or target mRNA

degradation [12]. The stability of the miRNA–mRNA interaction is critical for

repressing the potential target [13]. Each mRNA could be targeted by different

miRNAs and a single miRNA may target different mRNAs [14, 15]. Gene

expression silencing by means of miRNAs and changes in the miRNA

expression level regulate various biological processes, including the

differentiation, maturation, function of immune cells and maintenance of

immune homeostasis [16-19]. MDSCs , an immune-suppressive cell, plays an

important role in a wide range of human diseases including cancer, chronic

inflammatory and autoimmune diseases. Therefore, both abnormal expression

and function of miRNAs in MDSCs were investigated, so that Novel miRNAs

regulatory mechanisms on MDSCs were displayed.

MicroRNAs regulate the differentiation and activation of tumor MDSCs

1. miRNAs up-regulation on tumor MDSCs

Recent reports demonstrated that miR-494 expression in tumor MDSCs was

dramatically induced by tumor-derived factors, such as TGF-β1 to regulate the

accumulation and activity of MDSCs by targeting of phosphatase and tensin

homolog (PTEN) and activation of the Akt pathway [20]. miR-10a activate

AMPK signaling to promote expansion and activation of MDSCs in breast

cancer cells with chemotherapy-induced immune resistance [21]. miR-6991-

3p could directly target the immune checkpoint gene LGALS9 and MiR-6991-

3p mimic transfection suppressed expansion and promoted apoptosis of

MDSCs through suppressing LGALS9-mediated activation of STAT3 [22]. In B

lymphoma -bearing mice, miR-30a expression was increased in both G-MDSCs

and M-MDSCs. After the transfection of miR-30a mimics, the differentiation and

suppressive abilities of MDSCs were increased via up-regulation of arginase-

1. miR-30a also down-regulated suppressor of cytokine signaling 3 (SOCS3)

mRNA to activate STAT3 signaling to promote MDSC differentiation and

suppressive activities, indicating that same individual microRNA can regulate

differentiation and activity of MDSCs through difference pathways [23, 24]

(Figure1). The inhibition of miR-9 promoted the differentiation of MDSCs with

significantly reduced immunosuppressive function via by targeting the runt-

related transcription factor 1 (Runx1), an essential transcription factor in

regulating MDSC differentiation and function [25] (Figure2).

2. Inhibitory roles of miRNAs on tumor MDSCs.

miRNAs also negatively mediate the differentiation and activity of tumor

MDSCs. The overexpression of miR-17 family members such as miR-17-5p,

miR-20a and miR-106a in human progenitor cells represses AML1 by binding

to its promoter, which results in the down-regulation of M-CSFR, thus limiting

MDSC differentiation [26] (Figure2). In LLC and ovarian carcinoma models,

miR-223 suppresses differentiation and accumulation of MDSCs by targeting

molecule myocyte enhancer factor 2C (MEF2C) [27]. miR-142-3p can prevent

MDSC differentiation during tumor-induced myelopoiesis by modulating STAT3

and C/EBPβ signal pathway, indicating that the potential therapeutic application

for miR-142-3p oligonucleotide as adjuvant tool for adoptive T cell therapy of

cancer [28] (Figure1).

3. miRNAs from tumor-derived extracellular vesicles

extracellular vesicles (EVs) were involved in miRNAs regulation on MDSCs.

Cancer cells secreted EVs, which were involved in the intercellular transfer of

proteins, lipids, and genetic material (such as miRNAs). Those tumor-

associated EVs represented an ideal candidate due to their ability to recirculate

in body fluids during the process of MDSC generation from bone marrow in

tumor microenvironment[29-31]. In melanoma patients, some miRNAs (such as

miR-99b, miR-100, miR-125a/-125b, miR-146a/-146b, miR-155, let-7e), which

are highly detected in plasma as associated with EVs, mediate the generation

and functional features of tumor M-MDSCs [8, 32, 33]. In Acute myeloid

leukemia (AML), miR-34a promotes the expansion of MDSCs as the regulatory

mechanism by which MUC1 drives c-myc expression in Acute AML cells and

tumor-derived EVs [30]. In addition, miR-34a also inhibited the apoptosis of

MDSCs via targeting N-myc [34] or p2rx7/Tia1 [35] (Figure2). Those data

suggested that miR-34a upregulated the generation and accumulation of tumor

MDSC through different pathways as many other miRNAs.

4. miRNAs from tumor-derived exosomes

Exosomes derived from tumor (such as gliomas) are also involved in MDSC

differentiation. In glioma-bearing mice, glioma-derived exosomes (GDEs)

facilitate the expansion and function of MDSCs. Hypoxia promoted the

upregulation of miR-10a and miR-21 expression in GDEs to induce MDSC

activation by targeting the IκBα/NF-κB and PTEN/PI3K/AKT pathways. The

reduced numbers of MDSCs were observed in the spleens of mice bearing miR-

10a or miR-21 knockout glioma cells, compared with those in bearing glioma

cells [36]. Those GDEs also regulated the expansion of MDSCs through

miRNA-29a/Hbp1 and miRNA-92a/Prkar1a pathways [37], indicating that

GDEs can regulate MDSC expansion through difference miRNAs (Table1).

miRNAs mediate the function of MDSCs in tumor microenvironment

1. miRNAs regulate MDSCs through Stat3 pathway

We ever discussed the findings about the relationship between miRNAs and

JAK/STAT3 in cancer [2, 8]. Recently, there were more emerging data about

negative and positive regulation of miRNAs networks and JAK/STAT3 signaling

pathways via direct and indirect regulatory mechanisms in tumor

microenvironment (Figure 1). STAT3, as an important transcript factor, is also

required for the suppressive function of tumor MDSCs [2, 38-40]. Therefore, we

focus on the regulation of miRNAs on tumor MDSC through JAK/STAT3 further.

Recent data demonstrated that four members of miR-17 family (including miR-

17, miR-20a, miR-93, miR-106a) played inhibitory roles in the function of tumor

MDSCs. In tumor microenvironment, tumor-associated factors downregulate

the expression of miR-17-5p and miR-20a and promote the Stat3-associated

suppressive function of MDSCs [41]. Thus, miR-17-5p and miR-20a can

potentially be used as targets in immunotherapy strategies to inhibit the function

of MDSCs via reducing STAT3 expression[42].

The enhanced expression of miR-142-3p reduced the immunosuppressive

activity of tumor BM-MDSCs, restoring CD8+ T cell proliferation through

inhibiting C/EBPβ/STAT3 pathway [28]. miR223 and Let7e also downregulate

the suppressive function of MDSCs through inhibiting the activation of STAT3

in Gliomas [41]. The expression of PD-L1 on tumor MDSC, which are closely

related to the suppressive function of MDSCs, was regulated by the miR-

93/106b miRNA cluster of miR-17 family through stat3 pathway. Those PD-L1

expression levels on MDSCs can be reduced significantly after treatment of

miR-93 mimics [43, 44]. Therefore, those miRNAs above regulate tumor

MDSCs plasticity through inhibiting STAT3 pathways (Figure1).

The regulatory roles of miRNAs on tumor MDSCs are positively involved in

STAT3 pathway. miR-200c promotes suppressive potential of tumor MDSCs by

targeting PTEN/friend of Gata 2 (FOG2), which can lead to STAT3 and

PI3K/Akt activation [45]. miR-155 and miR-21 showed a synergistic effect on

MDSC induction via targeting SHIP-1 and PTEN respectively, leading to Stat3

activation [46]. In a line with this finding above, MDSCs was shown to require

miR-155 to facilitate tumor growth [47]. However, recent study revealed the loss

of miR-155 in MDSCs enhanced its recruitment and function in solid tumor,

which is not consistent with the results above [11, 48].

2. miRNAs regulate MDSCs through PD-L1/PD-1 pathway

The immunotherapy of checkpoints PD-L1/PD-1 on tumor have been broadly

applied and those Checkpoints were also associated with the tumor MDSCs [1,

8]. But the interaction between miRNAs and checkpoints PD-L1/PD-1 on tumor

MDSCs was recently investigated. Some scientists reported that five members

of miR-15 family, which include miR-15a, miR-15b, miR-16, miR-195 and miR-

503, activate T cell response by inhibiting the function of MDSCs and/or Tregs

in the tumor microenvironment through blocking PD-L1/PD-1 signaling pathway

[42, 45, 49, 50], however, miR-424(322), another member of miR-15 family was

inversely correlated with PD-L1 pathways. High levels of miR-424(322) in the

tumor were positively correlated with the function of MDSCs and Tregs [51]

(Figure2). The latest results demonstrated that hypoxic tumor-derived

exosomes (TEXs) enhanced the suppressive roles of MDSCs on γδ T cells

through a miR-21/PTEN/PD-L1 pathway in oral squamous cell carcinoma

(OSCC) [52]. Thus, interaction between miRNAs network and PD-L1/PD-1

regulates the expansion and function of tumor MDSCs, providing one novel

therapy method for inhibiting MDSC-associated tumor metastasis (Table 2).

3. miRNAs regulate MDSCs through other molecular pathways

miRNAs networks regulate the function of MDSCs through other target genes.

Recent studies demonstrated that EL-4 tumor-elicited MDSCs showed

increased expression of miR-690 with attenuated C/EBPα expression [50].

Hypoxia-induced miR-210 enhanced the immunosuppressive activity of tumor

MDSCs by increasing arginase activity, nitric oxide production and IL-16 [53].

It was reported that the expansion of tumor MDSCs was regulated by miR-494

through PTEN/AKT. The downregulation of PTEN by miR-494 enhanced the

activity of AKT to promote the accumulation of MDSCs in tumor tissues [20].

miR-492 also play similar roles in the suppressive function of MDSCs[54]. In

melanoma patients, several miRNAs (including miR-100 family member-miR-

99b/-100 and miR-125 family members-miR-125a/-125b) induced the activity

and accumulation of MDSCs through IL-6 and CCL2, activating JAK/STAT3

pathway further [32] (Figure1).

MicroRNAs regulate the expansion and function of MDSCs in

inflammation, infection and autoimmune diseases

1. Inflammation and infection

MDSCs also play an important role in other pathological conditions, including

inflammation, infection and autoimmune diseases [2, 10, 55]. Thus, we

examined if miRNAs had regulatory roles on MDSCs in those diseases. In

mouse model with chronic asthma, miR-20b Induced the increased numbers of

MDSCs in lung through TGF-β to inhibit airway inflammation[56]. MDSCs

enhance late sepsis development through immunosuppressive function in

mice. miR-375 can regulate the function and miR-21 expression of those

MDSCs through targeting Janus kinase 2 (JAK2) and further impaired STAT3

in the mice with sepsis [57]. miR-21 and miR-181b couple with NFI-A to

promote immunosuppression of MDSCs for improving late-sepsis survival [58].

The overexpression of some miRNAs is induced by the synergistic effect of

STAT3 and C/EBPβ, which activate miR-21 and miR-181b promoters after

sepsis initiation [59]. The latest results demonstrate that S100A9 stabilizes

those STAT3/C/EBPβ protein complex to promote MDSC expansion and

immunosuppression in late/chronic sepsis by inducing the expression of miR-

21 and miR-181b [60]. In inflammation environment, TNFα-mediated miR-136

also target NFI-A to induce differentiation and activity of MDSCs [61]. MDSCs

and Tregs were developed during chronic hepatitis C virus (HCV) infection.

miR-124 downregulated the expression level of STAT3, as well as TGF-β,

which were overexpressed in MDSCs to reduce the frequencies of MDSCs and

Tregs , thus uncovering a novel mechanism for the expansion of MDSC and

Tregs during HCV infection [62].

2. Autoimmune Disease

Recent studies demonstrated that MDSCs are involved in autoimmune

diseases. In experimental autoimmune encephalomyelitis (EAE), MDSCs can

suppress T cell activities, in which miR-223 downregulate the number and

function of MDSCs via STAT3. In miR-223 knockout mice, MO-MDSCs

suppressed T cell proliferation in vitro and EAE in vivo more than wild-type MO-

MDSCs[63] (Table 3).

Concluding remarks

MDSCs are one of important immune suppressive cells in tumor

microenvironment and may be next breakthrough target for tumor

immunotherapy [5, 6, 64]. The expansion and function of tumor MDSCs have

been widely investigated, however, the regulatory mechanism of MDSCs need

be further defined[5, 55, 65]. Recently, the novel research field of miRNA

regulation on tumor MDSCs plasticity were opened[32, 66, 67]. The

differentiation and function of MDSCs seems to be regulated by multiple

miRNAs, some of which were classified by us based on their family members,

in order that the scientists may investigate the regulatory roles of other related

members of miRNAs family on tumor MDSCs. However, it remains to be

clarified how those dysregulated miRNAs were combined in vivo to act on

MDSCs on key signaling pathway. In addition, most of research data about

miRNA function on tumor MDSCs were gained from murine studies, even

though there are a few miRNA data from human patients with cancer. The

significant and application of miRNAs for the expansion and function of MDSCs

in patients with cancer need be further investigated. Therefore, the interaction

of dysregulated miRNAs on MDSCs with transcription factors, cofactors and

chromatin modifiers may target specific miRNA-regulated pathways to provide

novel ways to treat MDSCs in tumor microenvironment.

Acknowledgements

This work was supported by National Natural Science Foundation of China

(Grant No. 81572868); Natural Science Foundation of Shangdong (Grant No.

ZR2014ZM023). Jilin province science and technology development program

(20160201001YY, 20170520043JH); Foundation of Jilin Educational

Committee (JJKH20170726KJ); Intramural Research Program at the NCI.

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Figure1. The interaction between microRNAs and Stat3 in tumor microenvironment.

MicroRNAs (miRNAs) are emerging as direct or indirect regulators of Janus Kinase (JAK)–

Signal Transducer and Activator of Transcription 3 (STAT3) pathways in the pathogenesis of

cancer. In each process, microRNAs networks play positive (black line) or negative (orange

line) roles. SOCS1: Suppressor Of Cytokine Signaling 1; SOCS3: Suppressor Of Cytokine

Signaling 3; PTEN: Phosphatase and Tensin Homologue; ZEB1: Zinc Finger E-Box Binding

Homeobox 1; EGFR: Epidermal Growth Factor Receptor.

Figure2. Effect of microRNA networks on MDSCs’ differentiation, expansion,

activation and function in tumor microenvironment.

In tumor microenvironment, MDSCs from Immature myeloid cells are divided as two

subtypes: monocytic MDSCs (M-MDSCs) and Granulocytic MDSCs (G-MDSCs),

which utilize different suppressive mechanism to inhibit the antitumor ability of T

cells. In each process, microRNAs networks play positive (black line) or negative

(orange line) roles.

Table 1. microRNAs regulation on the differentiation and expansion of tumor

MDSCs

MicroRNAs Target genes References

miR-9 Runx1 [25]

miR-10a AMPK [21]

miR-10a/-21 Rora/NF-κB [36]

miR-17-5p/-20a (miR-17 family) AML1 [26]

miR-106a (miR-17 family) AML1 [26]

miR-30a SOCS3/Stat3 [24]

miR-34a MUC-1 [30]

miR-34a N-myc [34, 35]

miR-92a Prkar1a [37]

miR-125b TNF [8]

miR-146a CSF-1R [33]

miR-142-3p C/EBPβ/Stat3 [28]

miR-155 C/EBPβ [46, 47]

miR-223 MEF2C [27]

miR-494 PTEN [20]

miR-6991-3p Stat3 [22]

Table 2. microRNAs mediate the function of MDSCs in tumor

microenvironment

MicroRNAs Target genes References

miR-15a (miR-15 family) PD-1/PD-L1 [50]

miR-16/195 (miR-15 family) PD-1/PD-L1 [49]

miR-503 (miR-15 family) PD-1/Stat3 [42]

miR-424(322) (miR-15 family) PD-1/PD-L1 [51]

miR-17-5p/-20a (miR-17 family) Stat3 [42]

miR-93/-106b (miR-17 family) Stat3 [43, 44]

miR-21 Stat3 [46]

miR-21 PTEN/PD-L1 [52]

miR-99b/-100 (miR-100 family) IL-6/CCL2 [32]

miR-125a/-125b (miR-125 family) IL-6/CCL2 [32]

miR-136 NFIA [61]

miR-142-3p C/EBPβ/Stat3 [28]

miR-155 Stat3 [11, 46]

miR-155 MCL-1 [48]

miR-200C PTEN/FOG2 [45]

miR-210 NO production [53]

miR-223 Stat3 [41]

miR-492 PTEN [54]

miR-494 PTEN [20]

miR-690 C/EBPa [50]

Let7e Stat3 [41]

Table 3. microRNAs regulate the expansion and function of MDSCs in

inflammation, infection and autoimmune diseases

MicroRNAs Diseases/ MDSC plasticity Target genes References

miR-20b Asthma/Expansion TGFβ [56]

miR-21 Sepsis/Expansion NFI-A [58]

miR-124 HCV/Suppressive function Stat3 [62]

miR-136 Inflammation/ differentiation NFI-A [61]

miR-181b Sepsis/ Expansion NFI-A [58]

miR-223 EAE/Suppressive function Stat3 [63]

miR-375 Sepsis/Expansion Jak2-stat3 [57]